Genomic landscapes of early-onset versus average-onset colorectal cancer populations.

Abstract

3536 Background: Early-onset colorectal cancer (eoCRC, initial CRC diagnosis at age < 50 years) has been increasing in the past two decades especially in Western countries. This study evaluates somatic and germline profiles in eoCRC compared to average-onset CRC (aoCRC, initial CRC diagnosis at age ≥ 50 years). Methods: This is a retrospective, cross-sectional study utilizing data from de-identified records of colorectal cancer patients tested with the Tempus xT assay from 2017 to 2022. Briefly, the assay is a targeted panel that detects single nucleotide variants, insertions and/or deletions, and copy number variants in 598-648 genes, as well as chromosomal rearrangements in 22 genes with high sensitivity and specificity. Baseline characteristics and immunologic markers were compared between eoCRC and aoCRC by Wilcoxon Rank Sum or Chi-squared test (reporting p-values). Somatic and germline mutations were compared between two age groups with false discover rate adjustments (reporting q-values). Results: In this study, 2,379 eoCRC and 8,627 aoCRC patients were included, with the majority diagnosed with stage IV disease. Additionally, germline alterations were assessed on a subset of 6,311 patients with tumor/normal match testing (eoCRC = 1,413 and aoCRC = 4,898). Left-sided primaries were more common in eoCRC (85% left/rectum in eoCRC vs. 75% left/rectum in aoCRC (p < 0.001), and rates of microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) were lower compared to aoCRC (4.2% vs. 6.8%, p < 0.001). eoCRC has a unique somatic mutation profile compared to aoCRC. A higher prevalence of germline mutations was observed in eoCRC overall (6.9% vs. 5%, p = 0.006); however, no statistically significant differences were observed in individual germline genes compared to aoCRC, likely due to relatively small numbers. Conclusions: eoCRC has a unique mutational profile and presence of germline mutations in 6.9% of eoCRC, indicating a potential role for universal germline testing in CRC. [Table: see text]

Synthetic Data Improve Survival Status Prediction Models in Early-Onset Colorectal Cancer

“…Models were fine-tuned for optimal hyperparameters during the training and validation. Specifically, for Decision Tree and Random Forest, we set the maximum depth at (2,4,5,7,9,10) and the minimum samples split at (2,3,4). For the XGBoost, the chosen maximum depth parameters were (4, 5, 7, 10, 50), along with learning rates of (0.01, 0.1).…”

“…Colorectal cancer diagnosed in patients younger than 50 years, known as early-onset colorectal cancer (EOCRC), is believed to have distinct etiologic, genetic, and molecular profiles compared with colorectal cancer diagnosed at an average onset. [1][2][3] The rising prevalence of EOCRC in North America, Europe, Australia, and South Korea highlights its emergence as a public health concern. 4,5 However, it accounts for 10% of all colorectal cancer (CRC) cases, leading to a limited understanding of the disease.…”